Osteoporosis affects more than 200 million people worldwide. Therapeutic approaches to osteoporotic bone loss have focused on either anabolic or antiresorptive agents. However, there is a pressing need to develop new agents that target both bone formation and resorption. NELL-1 is a potent pro-osteogenic protein most studied for its local bone forming effects. Preliminary studies have suggested that NELL-1 also exerts a systemic, protective function against osteoporotic bone loss via modulating both osteoblast and osteoclast activity. These cellular effects of NELL-1 appear to occur in large part via activation of Wnt/-catenin signaling. Excitingly, we have recently identified the presence of two NELL-1 isoforms (NELL-1570 and NELL-1810) - of which the former demonstrates significantly greater bone forming effects. This has led to our central hypothesis that NELL-1 is a promising systemic therapeutic agent for osteoporosis with ability to (1) effectively reverse osteoporotic bone loss, and (2) regulate bone homeostasis by regulating osteoblast (OB) and osteoclast (OC) differentiation and activity via Wnt/-catenin signaling. Furthermore, we anticipate that the shor isoform of NELL-1 (NELL-1570) will demonstrate more potent in vivo anabolic effects. We will test these hypotheses in two specific aims: AIM 1: Compare NELL-1570 and NELL-1810 for the systemic treatment of OVX-induced osteoporosis in mice. Our preliminary data show that systemic rNELL-1 (NELL-1810) reverses OVX-induced bone loss in mice. However, accumulating evidence suggests that NELL-1570 has significantly more potent effects on osteoprogenitor cell proliferation and differentiation. AIM 1 will directly compare systemic administration of NELL-1810 and NELL-1570. Through radiologic, histologic, histomorphometric and biomechanical analyses, we will examine bone density, formation, turnover and strength. AIM 2: Compare the isolated cellular effects of NELL-1570 and NELL-1810 on OB/OC progenitor cells and OB/OC activity. In parallel, AIM 2 will evaluate systemic rNELL-1 effects on the number and activity of stem cells, OB and OC cells, as well as Wnt/-catenin signaling. Cells will be isolated from animals after systemic treatment with NELL-1570 or NELL-1810, and examined by flow cytometry, proliferation and differentiation assays. Novel rNELL-1 based therapies can improve the current standard of care for the treatment of osteoporosis, and the prevention of osteoporotic fractures that cost $25 billion annually. As well, improved basic biological understanding of rNELL-1 regulation of Wnt signaling may lead to future therapies for other disease entities characterized by deregulated Wnt signaling.